Receptors for serotonin (5-hydroxytryptamine, 5-HT) are an important class of G protein-coupled receptors. Serotonin is thought to play a role in processes related to learning and memory, sleep, thermoregulation, mood, motor activity, pain, sexual and aggressive behaviors, appetite, neurodegenerative regulation, and biological rhythms. As expected, serotonin is linked to pathophysiological conditions such as anxiety, depression, obsessive-compulsive disorders, schizophrenia, suicide, autism, migraine, emesis, alcoholism and neurodegenerative disorders.
The serotonin receptors are currently classified into seven subfamilies (5-HT1 through 5-HT7). See, Hoyer, D., et al., “VII International Union of Pharmacology classification of receptors for 5-hydroxytryptamine”, Pharmacol. Rev., 56, 157-203 (1994). The subfamilies have been further divided into subtypes. For example, the 5-HT2 receptor is currently divided into three subtypes: 5-HT2a, 5-HT2b and 5-HT2c. These 5-HT2 receptor subtypes are linked to phospholipase C with the generation of two second messengers, diacylglycerol (which activates protein kinase C) and inositol trisphosphate (which releases intracellular stores of Ca2+). The choroid plexus, an epithelial tissue that is the primary site of cerebrospinal fluid production, contains very high density 5-HT2c receptors. See, Sanders-Bush, E. and S. E. Mayer, “5-Hydroxytryptamine (Serotonin) Receptor agonists and Antagonists”, Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapter 11, 9th Ed., McGraw-Hill, New York, N.Y. (1996).
Bishop, M. J. and Nilsson, B. M., “New 5-HT2c Receptor Agonists” Expert Opin. Ther. Patents, 2003, 13(11): 1691-1705, review patent applications that describe compounds having agonist activity at the 5-HT2c receptor. The review also addresses indications for which evidence exists to support the use of 5-HT2c agonists in their treatment, such as obesity, schizophrenia, anxiety, depression, obsessive-compulsive disorder, sexual dysfunction, epilepsy, and urinary incontinence, among others.
Julius, et al., isolated and characterized the 5-HT2c receptor and later reported that transgenic mice lacking the 5-HT2c receptor exhibit seizures and an eating disorder resulting in increased consumption of food (see, U.S. Pat. Nos. 4,985,352 and 5,698,766, respectively). Consequently, compounds selective for the 5-HT2c receptor may provide useful therapies for the treatment of seizure and eating disorders without the side effects typically associated with nonselectivity of the ligand.
Several compounds have been proposed as 5-HT2c receptor agonists or antagonists for use in the treatment of obesity and other related diseases associated with decreased neurotransmission of serotonin in mammals. See, e.g., EP 863136 (azetidine and pyrrolidine derivatives); EP 657426 (tricyclic pyrrole derivatives); EP 655440 (substituted 1-aminoethyl indoles); EP 572863 (pyrazinoindole derivatives); WO98/030548 (aminoalkylindazole compounds); WO 98/56768 (tricyclic pyrrole and pyrazole derivatives); WO 99/43647 (azetidine and pyrrolidine derivatives); WO 99/58490 (aryl-hydronaphthalenalkanamine derivatives); WO 00/12475 (indoline derivatives); WO 00/12482 (indazole derivatives); WO 00/12502 (pyrroloquinoline derivatives); WO 00/12510 (pyrroloindole, pyridoindole and azepinoindole derivatives); WO 00/28993 (naphthylacetylpiperazine derivatives); WO 00/44737 (aminoalkylbenzofuran derivatives); WO 00/76984 (2,3-disubstituted pyrazines); US Publication No. 2002/0147200 A1 or WO 02/40456 (pyrazine, pyridine, and pyrimidine derivatives); WO 03/000666 (pyrazine derivatives); and US Publication No. 2003/0105106 A1 or WO 03/000663 (pyrimidine derivatives). For a review of obesity medications, see A. Halpern and M. C. Mancini, “Treatment of obesity: an update on anti-obesity medications,” Obesity Reviews, 4, 2542 (2003).
Schizophrenia is a complex multifactorial illness caused by genetic and non-genetic risk factors that produce a wide variety of symptoms. Historically, the disease has been characterized by positive and negative symptoms. The positive symptoms include delusions and hallucinations and the negative symptoms include apathy, withdrawal, lack of motivation and pleasure. More recently, deficits in affect, attention, cognition and information processing have been recognized as key pathologies in this complex disorder. No single biological element has emerged as a dominant pathogenic factor in this disease. It is likely that schizophrenia is a syndrome that is produced by the combination of many low penetrance risk factors. The symptoms of schizophrenia, however, are correlated with enhanced dopamine neurotransmission in the mesolimbic system.
A 5-HT2c agonist was shown to have activity in pre-clinical models of depression (rat forced swim test, learned helplessness, olfactory bulbectomy model, resident-intruder model). Antidepressant-like Effects of the 5-HT2c Selective Agonist WAY-163909 in Rodents. Rosenzweig-Lipson S., et al., Poster at the Society for Neuroscience 34th Annual Meeting, San Diego, 2004; Society for Neuroscience Abstracts 2004, 34: San Diego (Abs 394.6). 5-HT2c agonists may improve the negative symptoms and apathy associated with schizophrenia. The selective 5-HT2c agonist of Rosenzweig-Lipson S., et al. has also been reported to exhibit an atypical antipsychotic-like profile in rodent behavioral models. WAY-163909, A 5-HT2c Agonist, Exhibits an Atypical Antipsychotic-Like Profile in a Battery of Rodent Behavioral Models. Grauer, S., et al., Poster at the Society for Neuroscience 34th Annual Meeting, San Diego, 2004; Society for Neuroscience Abstracts, 2004, San Diego (Abs 394.7). A rationale for the treatment of schizophrenia recognizes that 5-HT2c agonists selectively decrease firing and release of dopamine in the mesolimbic dopaminergic pathway. Grauer, S., et al., supra.
It is notable that the 5-HT2c agonist studied by Rosenzweig-Lipson S., et al. and Grauer, S., et al., supra, is reported to produce a dose-dependent reduction of food intake in rats. Pharmacological Characterization of WAY-163909, a Novel 5-HT2c Receptor Selective Agonist. Dunlop, J., et al., Poster at the Society for Neuroscience 34th Annual Meeting, San Diego, 2004; Society for Neuroscience Abstracts 2004, San Diego (Abs 394.10).
Toxicity and non-selectivity of ligands for the various 5-HT receptors remain a challenge. It is suspected that the non-selectivity of some ligands contributes to various adverse side effects such as hallucinations and cardiovascular complications. Therefore, there remains a need for 5-HT2c selective receptor ligands.